OZONE TOXICITY

Air Quality Information Louisville, Kentucky. Available for All States and Regions.
http://services.louisvilleky.gov/MetroAirNet/AQI.aspx

Medline Abstracts OZONE
http://www.ophsource.org/periodicals/ophtha/medline/related/MDLN.13200782
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Kentucky High School First Official Football Practice is July 15. Full Pads Aug 1, 2010
Hazardous Weather Watch for Metro Louisville, KY, Year 2010:

Metro Louisville, KY
2010____AQI____Temp__Polutant
July 5___129____93*____PM2.5
July 7___125____96*____Ozone
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OZONE TOXICITY is a well known toxic condition affecting both human and plant life. Because Air Quality Standards for exposure are exceeded in many American cities and regions and because those dangerous exposures are resulting in increased morbidity and mortality, Ozone Toxicity is the focus of considerable attention and research. The affect of Ozone Toxicity on Exercising Athletes is a paramount concern in Air Polluted communities.
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OZONE TOXICITY
“New statistics from the World Health Organization show that in the United States, air pollution annually kills nearly twice as many people as do traffic accidents and that deaths from air pollution equal deaths from breast cancer and prostate cancer combined,” said Tiffany Schauer, executive director of Our Children’s Earth Foundation.
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The following is one of many research articles about OZONE TOXICITY, a concisely written abstract with terms for the introduction to the disorder.

Title: Mechanisms of Ozone Toxicity, Author SOO, CAROL Degree MS, University of Cincinnati, Medicine : Environmental Health Sciences, 2002. Advisor Dr. George D. Leikauf Abstract:

“Ozone is formed as a secondary air pollutant in the atmosphere from the photochemical reaction of reactive hydrocarbons, nitrogen dioxide, and sunlight. Ozone is a potent lung irritant that can cause reductions in lung function and increases in respiratory symptoms, airway reactivity, inflammation, and permeability.”

“Large portions of the United States exceed the air quality standard of exposure. Ozone is so reactive that it degrades macromolecules (ozonolysis) on the airway surface before entering the cell. Toxicity is thus due, in part, to secondary products formed by ozonolysis.”

“The reaction of ozone with unsaturated fatty acids in the extracellular fluid and plasma membranes yield aldehydes and hydroxyhydroperoxides. Further degradation of the hydroxyhydroperoxide in aqueous solution yields a second aldehyde and hydrogen peroxide. These aldehydes and hydroxyhydroperoxides may be three to nine carbons in length and freed from the phospholipid molecule to exert effects elsewhere.”

“Toxicity may depend on chain length or saturation, assuming that the toxicity results from disruption of the cell membrane. Alternatively, the aldehydes and hydroxyhydroperoxides can be retained in the phospholipid molecule. Evaluation of colony forming efficiency assay on the aldehydes, hydroxyhydroperoxides, and phospholipids will provide a better understanding of the toxic effects of ozonolysis products on the airway epithelium.”
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OZONE
Ozone (O3) is a tri-atomic molecule, consisting of three oxygen atoms. It is an allotrope of oxygen that is much less stable than the di-atomic allotrope (O2). Ozone in the lower atmosphere is an air pollutant with harmful effects on the respiratory systems of animals and will burn sensitive plants; however, the ozone layer in the upper atmosphere is beneficial, preventing potentially damaging ultraviolet light from reaching the Earth’s surface.

Ground Level Ozone peaks in the afternoon after sunlight has had the opportunity to “cook” a soup mixture of air-born nitrogen oxides, volatile organic compounds. and sulphur dioxide. They also peak just after mid-day from Air Pollution emitted that day.

Ozone is a powerful oxidizing agent, far stronger than O2. It is also unstable at high concentrations, decaying to ordinary diatomic oxygen (in about half an hour in atmospheric conditions):[9]
2 O3 → 3 O2

This reaction proceeds more rapidly with increasing temperature and increased pressure. Deflagration of ozone can be triggered by a spark, and can occur in ozone concentrations of 10 wt% or higher.[10] Wikipedia
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OZONE TOXICITY
The Symptoms
How does ozone affect my health?
There is lots of good, scientific research concerning the effect of ozone on people. Ozone can affect your lungs and respiratory system in several ways.

• Ozone can irritate your respiratory system. This might come in the form of coughing or an uncomfortable feeling in your chest. Symptoms may last a few hours after exposure.

• Ozone can impair your ability to breathe. You may not be able to breathe in as much as air as you are normally able to. Your breathing might be more rapid and shallow.

• Ozone can aggravate asthma. Doctors report that high ozone levels result in a greater number of asthma attacks. That’s because asthmatics are more greatly affected by the irritant. Ozone also makes you more sensitive to allergens that cause asthma attacks. Ozone can also aggravate chronic lung diseases like emphysema and bronchitis.

• Ozone can inflame and damage the lining of your lungs. Ozone can damage the cells that line your lungs. Eventually, these damaged cells are replaced. But, repeated damage may result in permanent problems.

These are all short-term health effects. Scientists are researching ozone’s long-term effects. There is a concern that the developing lungs of children repeatedly exposed to high levels of ozone may be damaged. Some studies in animals suggest that ozone may also harm the ability to fight off respiratory infections.

Who is most likely to be harmed by ozone?

Children, adults who are active outdoors, and people with respiratory diseases are most likely to be harmed by high levels of ozone. Some people who don’t fall into any of these categories are apparently more sensitive to ozone and also suffer problems.

What are the symptoms of ozone exposure?

You may cough or have impaired or painful breathing. People with emphysema or bronchitis may see a worsening of symptoms.

Are there always symptoms from exposure to ozone?

No. Ozone damage can occur without any noticeable signs. People who live in areas where ozone levels are frequently high may find that their initial symptoms go away over time, particularly when exposure to high ozone levels continues for several days. Ozone continues to cause lung damage even when the symptoms have disappeared. The best way to protect your health is to find out when ozone levels are elevated in your area and take simple precautions to minimize exposure even when you do not feel obvious symptoms.

What are the health effects that are associated with the different levels of the Air Quality Index?

Air Quality Health Effects
Good
AQI: 0-50
(Green) •No health effects are expected.

Moderate
AQI: 51-100
(Yellow) What are the possible health effects?
Unusually sensitive people (active children and adults, people with respiratory disease, such as asthma, and others who are unusually susceptible) should consider limiting prolonged outdoor exertion.

What can I do to protect my health?

When ozone levels are in the moderate range, consider limiting prolonged outdoor exertion between 2 p.m. and 6 p.m. if you are unusually sensitive to ozone.
Unhealthy for Sensitive Groups

AQI: 101-150
(Orange) What are the possible health effects?
If you are a member of a sensitive group, you may experience respiratory symptoms (such as coughing or pain when taking a deep breath) and reduced lung function, which can cause some breathing discomfort.

What can I do to protect my health?

If you are a member of a sensitive group, limit prolonged outdoor exertion. In general, you can protect your health by reducing how long or how strenuously you exert yourself outdoors and by planning outdoor activities when ozone levels are lower (usually in the early morning or evening).

You can check with your State air agency to find out about current or predicted ozone levels in your location. This information on ozone levels is available on the Internet at http://www.epa.gov/airnow/.
Unhealthy

AQI: 151-200

(Red) What are the possible health effects?

At this level, anyone could experience respiratory effects. If you are a member of a sensitive group, you have a higher chance of experiencing respiratory symptoms (such as aggravated cough or pain when taking a deep breath), and reduced lung function, which can cause some breathing difficulty.

What can I do to protect my health?

If you are a member of a sensitive group, avoid prolonged outdoor exertion. Everyone else, especially children, should limit prolonged outdoor exertion.

Plan outdoor activities when ozone levels are lower (usually in the early morning or evening)

You can check with your State air agency to find out about current or predicted ozone levels in your location. This information on ozone levels is available on the Internet at http://www.epa.gov/airnow/.

Very Unhealthy
AQI: 201-300
(Purple) Sensitive and healthy individuals likely to experience moderate to severe effects like cough, painful and impaired breathing, and lung function Sensitive groups -avoid outdoor activity Healthy population -limit outdoor exertion -avoid outdoor exposure 2:00 PM to 6:00 PM
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OZONE TOXICITY TO HUMAN LUNGS CAUSES ARDS
(ACUTE RESPIRATORY DISTRESS SYNDROME)

To date, there are no specific pharmacological interventions of proven value for the treatment of ARDS. Although corticosteroids and prostaglandin E1 have been widely used clinically, recent studies have failed to show any benefit in outcome, lung compliance, pulmonary shunts, chest radiograph, severity score or survival.
24, 25, 26, 27 The Internet Journal of Emergency and Intensive Care Medicine™ ISSN: 1092-4051, 1997 Volume 1 Number 1
The Acute Respiratory Distress Syndrome
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Ground-level ozone formation, that is mainly created by burning fuels, increases at higher ambient temperatures.

“Although people have no choice but to breathe the air around them, they do have choices that can help them stay healthy:

1. Stay indoors or be less active on poor air quality days.
2. Avoid high-traffic and highly industrialized areas whenever possible.
3. Support collective efforts and take individual steps that reduce air pollution.”

Such actions are a positive response to a problem that can literally steal one’s breath away.[Windows of the Universe, Ozone and Human Health]

Acclimatization or acclimation is the process of an organism adjusting to change in its environment, allowing it to survive changes in temperature, water and food availability, other stresses and often relates to seasonal weather changes. Acclimatization occurs in a short time, (days to weeks) and within one organism’s lifetime (compare adaptation). This may be a discrete occurrence or may instead represent part of a periodic cycle, such as a mammal shedding heavy winter fur in favor of a lighter summer coat.

Acclimation is an important characteristic among many organisms because it allows them to evolve over time while changes are also simultaneously occurring in their environment. Organisms adjust their morphological, behavioral, physical, and/or biochemical traits in response to these environmental changes that they are faced with.
When humans move from a cool or temperate environment to a hot, dry desert environment or vice versa, they should spend up to seven days acclimatizing to the change in their environment. This lets the body make internal adjustments (see homeostasis) to compensate for the change in environmental conditions. The same is true for sports participation.

If people do not acclimatize, then the person is at higher risk of heat related injuries (heat stroke, heat cramp). A heat acclimatized person will begin to sweat earlier and more intensely under heat, have a lower heart rate, and a lower skin temperature. The salt content of sweat also decreases as people acclimatize. Athletes from 50 years ago probably were better acclimated.

Acclimatization to high altitude continues for months or even years after initial ascent, and ultimately enables humans to survive in an environment that, without acclimatization, would kill them. Humans who migrate permanently to a higher altitude naturally acclimatize to their new environment by developing an increase in the number of red blood cells to increase the oxygen carrying capacity of the blood, in order to compensate for lower levels of oxygen in the air.
But humans cannot acclimate to the oxidation of body tissues by Ozone Toxicity. Permanent damage is the result of oxidation by Ozone Toxicity under certain circumstances such as Exercise to Exhaustion in Heated Ozone.
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Protein oxidation at the air-lung interface
Journal Amino Acids ; Publisher Springer Wien ; ISSN 0939-4451 (Print) 1438-2199 (Online) ; Issue Volume 25, Numbers 3-4 / December, 2003 ; Category Review Article ; DOI 10.1007/s00726-003-0024-x ;Pages 375-396 ;Subject Collection Biomedical and Life Sciences ; SpringerLink Date Thursday, February 19, 2004
Protein oxidation at the air-lung interface
F. J. Kelly1 and I. S. Mudway1

(1) Air Pollution and Health Research Group, School of Health & Life Sciences, Kings College London, London, United Kingdom, GB
Received: 28 December 2002 Revised: 1 January 2003 Accepted: 8 May 2003 Published online: 31 July 2003

Summary. Whilst performing its normal functions the lung is required to deal with a range of toxic insults. Whether these are infectious agents, allergens or air pollutants they subject the lung to a range of direct and indirect oxidative stresses. In many instances these challenges lead to oxidative alterations of peptides and proteins within the lung. Measurement of protein oxidation products permits the degree of oxidative stress to be assessed and indicates that endogenous antioxidant defenses are overwhelmed. The range of protein oxidation products observed is diverse and the nature and extent of specific oxidation products may inform us about the nature of the damaging ROS (reactive oxygen species) and NOS. Recently, there has been a significant shift away from the measurement of these oxidation products simply to establish the presence of oxidative stress, to a focus on identifying specific proteins sensitive to oxidation and establishing the functional consequences of these modifications. In addition the identification of specific enzyme systems to repair these oxidative modifications has lead to the belief that protein function may be regulated through these oxidation reactions. In this review we focus primarily on the soluble protein components of within the surface liquid layer in the lung and the consequence of their undue oxidation.
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Inhaled ozone, in the absence of other environmental toxicants, promotes increased vascular dysfunction, oxidative stress, mitochondrial damage, and atherogenesis

Am J Physiol Lung Cell Mol Physiol 297: L209-L216, 2009. First published April 24, 2009; doi:10.1152/ajplung.00102.2009
1040-0605/09

This Article; Articles by Chuang, G. C.; Articles by Ballinger, S. W. PubMed Citation;Articles by Chuang, G.C.;Articles by Ballinger, S.W.

EDITORIAL FOCUS
Pulmonary ozone exposure induces vascular dysfunction, mitochondrial damage, and atherogenesis; Gin C. Chuang,1,2,* Zhen Yang,1,2,* David G. Westbrook,1 Melissa Pompilius,1 Carol A. Ballinger,2,3 C. Roger White,2,4 David M. Krzywanski,1,2 Edward M. Postlethwait,2,3 and Scott W. Ballinger1,2,3 ; 1Department of Pathology, Division of Molecular and Cellular Pathology, 2Center for Free Radical Biology, 3Department of Environmental Health Sciences, and 4Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
Submitted 27 March 2009 ; accepted in final form 22 April 2009
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Do you jog in smog? Air pollution is another factor to consider in your fitness program; American Fitness, May-June, 2002 by Paula Court
“While enjoying your daily run on a sunny afternoon, a burning sensation suddenly grips your chest. What is going on? Could you be coming down with a cold? Probably not; you are most likely feeling the effects of exercising in air pollution. Recent research shows exercising in polluted air is harmful to your health. Air pollution interferes with the workings of your heart and lungs, aggravates asthma and weakens your body’s ability to fight infections.

Athletes are in an especially high-risk group, for the dangers of air pollution, because of the increased amount of air taken into their body during exercise. According to the American Lung Association, athletes take in up to 20 times more air per minute while exercising. Therefore, if air is polluted, 20 times more pollutants come in contact with an athlete’s respiratory tract, reducing lung function and interfering with his or her performance. For example, exercising an hour in a moderate level of ozone and carbon monoxide can reduce lung function and temporarily decrease the blood’s oxygen carrying capacity. Moreover, breathing through your mouth prevents your body from using its best defense against pollution–your nose. The nose filters air before it enters your lungs.

Ozone, the main hazardous ingredient in smog, forms when sunlight reacts with automobile and industrial emissions. As sunlight intensifies in the morning, the concentration of ozone increases. Ozone begins accumulating at approximately 11 a.m. and peaks around 3 p.m. After sunset, ozone can no longer form, therefore, the concentration decreases.
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Mutagenic fingerprint of ozone in human cells
Soraia A. C. Jorgea, b, Carlos F. M. Menckb, Helmut Siesc, Martin R. Osborned, David H. Phillipsd, Alain Sarasin, a and Anne Starya

a Laboratory of Genetic Instability and Cancer, UPR 2169 CNRS, Institute of Cancer Research, 7 rue Guy Moquet, B.P.8, 94801 Villejuif Cedex, France
b Departmento de Microbiologia, Instituto de Ciências Biom dicas, Universidade de São Paulo, Av. Prof. Lineu Prestes, 1374, Ed. Biom dicas 2, São Paulo 05508-900, Brazil
c Department of Physiological Chemistry I, Heinrich-Heine University, D-40225 Düsseldorf, Germany
d The Institute of Cancer Research, Haddow Laboratories, Cotswold Road, Sutton, Surrey SM2 5NG, UK
Received 12 October 2001; revised 31 January 2002; accepted 12 February 2002. Available online 17 May 2002.

Abstract

Ozone is an important factor in urban pollution and represents a major concern for human health. The chemical reactivity of ozone toward biological targets and particularly its genotoxicity supports a possible link between exposure and cancer risk, but no molecular data exist on its mutagenic potential in human cells. Using a shuttle vector, we showed that ozone is indeed a potent mutagen and we characterized the mutation spectrum it produced in human cells. Almost all mutations are base substitutions, essentially located at G:Cs (75%), typical of reactive oxygen species (ROS), but occurring in a specific pattern, i.e. a similar extent of GC:TA (28%), GC:CG (23%) and GC:AT (23%). The targeted distribution of mutations and identification of hotspot sequences define the first molecular fingerprint of mutations induced by ozone in human cells. Possible applications derived from our results with respect to ozone genotoxicity should help determining quantifiable biomarkers of ozone exposure in human health, especially for carcinogenesis.

Dietary Restriction Mitigates Ozone-induced Lung Inflammation in Rats: A Role for Endogenous Antioxidants
Frank Kari, Gary Hatch, Ralph Slade, Kay Crissman, Petia P. Simeonova, and Michael Luster; Environmental Immunology and Neurobiology Section, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina; Health Effects Research Laboratory, U.S. Environmental Protection Agency, Research;Triangle Park, North Carolina; and Toxicology and Molecular Biology Branch, Health Effects Laboratory Division,
National Institute for Occupational Safety and Health, Morgantown, West Virginia

It is generally recognized that the nutritional, physiological, and pharmacological status of the host markedly impacts its sensitivity to environmental stressors (1–3). Excessive body weight is a significant risk factor in a number of diseases contributing to enhanced morbidity and mortality in humans including cardiovascular and neoplastic diseases. Dietary restriction, with concomitant body weight reduction, increases longevity and ameliorates a variety of spontaneous and chemical-induced pathologies in experimental models including spontaneous cancers and cardiovascular lesions (4, 5). Dietary modulation of these age-related pathophysiologies may be closely related to the fact that diet restriction exerts an antioxidant action against lipoperoxidation, free radical mediated glycation and DNA damage (6–8). Since pro-oxidant activity is one of the major contributors to inflammation, we hypothesized that dietary restriction would influence the response to inflammatory stimuli via modulation of the antioxidant status.Acute ozone (O3) inhalation results in transient airway inflammation and diminished pulmonary function in experimental animals and humans (9, 10). This response is characterized by quantifiable indicators in bronchoalveolar lavage fluid (BALF), including neutrophil infiltration, increased protein, generation of inflammatory cytokines, and the release of arachidonic acid metabolites (10). The increased BALF protein appears to result from plasma leakage through the alveolar-capillary barrier of the lung (11, 12). The primary target cells in the lung are thought to be type I and II epithelial cells where oxidative damage may initiate an inflammatory response (13). While O3 itself is not a radical, it initiates radical-mediated lipid peroxidation which is minimized by antioxidants such as vitamins C and E (14, 15).
The work reported here describes our efforts to study the effect of dietary restriction on pathophysiological and biochemical processes associated with O3 -induced lung inflammation. Thus, we have employed inhalation exposure to O 3 as an oxidative challenge to the lung, and measured inflammatory responses and endogenous antioxidant status. Further, by exposing animals to 18 O-labeled O3 ,subsequent quantitation of 18 O binding in various lung compartments provided dosimetric indices of the toxic insult to relevant targets. Our findings indicate that dietary restriction affords protection against ozone-induced toxicity via, at least in part, increases in ascorbate and glutathione concentrations in BALF.
Studies were undertaken to determine whether dietary restriction protects against acute pulmonary oxidant challenge. Male F344 rats were fed NIH-31 diet either ad libitum or at restricted levels equal to 75% that of ad libitum intake. After 3 wk of dietary adaptation, animals were exposed by inhalation to 2.0 ppm ozone (O 3) for 2 h or chamber air and evaluated for cellular and biochemical indices of pulmonary toxicity. Compared to air controls, bronchoalveolar lavage fluid (BALF) from O 3 exposed ad libitum fed rats contained increased protein (145 versus 380 mg/ml), PMN infiltration (0 versus 11%) and fibronectin (45 versus 607 U/ml). Diet restriction abrogated these indicators of pulmonary inflammation induced by ozone.Binding of 18
O3to BALF protein and cells was significantly decreased in diet restricted rats while BALF ascorbate and glutathione levels, but not a -tocopherol or urate, were elevated compared toad libitum fed rats. Taken together, these results indicate that dietary restriction affords protection against O3 -induced oxidant toxicity. Protection is mediated partially by increases in ascorbate in the fluid bathing the lung surface, thereby providing an antioxidant sink which minimizes the ability of O3 to reach biological targets.
Kari, F., G. Hatch, R. Slade, K. Crissman, P. P. Simeonova, and M. Luster. 1997. Dietary restriction mitigates ozone-induced lung inflammation in rats: a role for endogenous antioxidants. Am. J.
Respir. Cell Mol. Biol. 17:740–747.
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Res Rep Health Eff Inst. 1997 Jun;(78):39-72; discussion 81-99.
Effects of ozone on normal and potentially sensitive human subjects. Part II: Airway inflammation and responsiveness to ozone in nonsmokers and smokers.
Frampton MW, Morrow PE, Torres A, Voter KZ, Whitin JC, Cox C, Speers DM, Tsai Y, Utell MJ.
Department of Medicine, University of Rochester School of Medicine and Dentistry, NY, USA.

Exposure to ozone at levels near the National Ambient Air Quality Standard causes respiratory symptoms, changes in lung function, and airway inflammation. Although ozone-induced changes in lung function have been well characterized in healthy individuals, the relationship between airway inflammation and changes in pulmonary function have not been prospectively examined.

The purpose of this study was to determine whether individuals who differ in, lung function responsiveness to ozone also differ in susceptibility to airway inflammation and injury.

A secondary goal was to determine whether ozone exposure induces airway inflammation in smokers, a population known to have airway inflammation and an increased burden of toxic oxygen species.
Healthy nonsmokers (n = 56) and smokers (n = 34) were exposed to 0.22 parts per million (ppm)* ozone for 4 hours, with intermittent exercise, for the purpose of selecting ozone “responders” (decrement in forced expiratory volume in 1 second [FEV1] > 15%) and “nonresponders” (decrement in FEV1 < 5%).

Selected subjects then were exposed twice to ozone (0.22 ppm for 4 hours with exercise) and once to air (with the same exposure protocol), each pair of exposures separated by at least 3 weeks, in a randomized, double-blind fashion. Nasal lavage (NL) and bronchoalveolar lavage (BAL) were performed immediately after one ozone exposure and 18 hours after the other, and either immediately or 18 hours after the air exposure.

Indicators of airway effects in lavage fluid included changes in inflammatory cells, proinflammatory cytokines, protein markers of epithelial injury and repair, and generation of toxic oxygen species.
In the classification exposure, fewer smokers than nonsmokers were responsive to ozone (11.8% vs. 28.6%, respectively); an insufficient number of smoker-responders were identified to study as a separate group.

In the BAL study, all groups developed a similar degree of airway inflammation, consisting of increases in interleukins 6 and 8 (maximal immediately after exposure), and increases in polymorphonuclear leukocytes (PMNs), lymphocytes, and mast cells (maximal 18 hours after exposure). The increase in PMNs was inversely correlated with age (p = 0.013), but gender, nonspecific airway responsiveness, and allergy history were not predictive of inflammation.

Alveolar macrophage production of toxic oxygen species decreased after ozone exposure in nonsmokers; however, not in smokers.
Findings from nasal lavage did not mirror lower airway inflammatory responses in these studies.

We conclude that, in response to ozone exposure, smokers experienced smaller decrements in lung function and fewer symptoms than nonsmokers; however, the intensity of the airway inflammatory response was independent of smoking status or airway responsiveness to ozone.

Furthermore, the burden of toxic oxygen species following ozone exposure was greater for smokers than for nonsmokers. Subjects were young, healthy, and able to sustain exercise; the results may not be representative of nonsmokers or smokers in general.
Nevertheless, the findings indicate that measuring symptoms and spirometric changes is not sufficient to assess the potential risks associated with ozone exposure, Fibroproliferation and mast cells in the acute respiratory distress syndrome (ARDS).
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J. Liebler, Z. Qu, B. Buckner, M. Powers, and J. Rosenbaum
Department of Medicine, Oregon Health Sciences University, Portland 97201-3098, USA.

This article has been cited by other articles in PMC.
Abstract BACKGROUND—Mast cells (MCs), which are a major source of cytokines and growth factors, have been implicated in various fibrotic disorders. To clarify the contribution of MCs to fibrogenesis, lung tissue from patients with the acute respiratory distress syndrome (ARDS) was examined during exudative through to fibroproliferative stages.

METHODS—Lung tissue was obtained from 17 patients with ARDS who had pathological features of the early exudative stage (n = 6) or the later reparative stages (n = 11), from four patients with idiopathic pulmonary fibrosis, and from three patients with normal lung tissue. Immunohistochemical localisation of tryptase (found in all human MCs), chymase (found in a subset of human MCs), α-smooth muscle actin (identifies myofibroblasts), and procollagen type I was performed.

RESULTS—Normal lung tissue exhibited myofibroblast and procollagen type I immuno-localisation scores each of <5 and MC scores of 1. Increased scores were defined as myofibroblast and procollagen type I scores of >10 and MC scores of 2. Eighty percent of lung tissue samples from the early exudative stage of ARDS exhibited increased numbers of myofibroblasts, 50% had increased numbers of procollagen type I producing cells, while only 17% had increased numbers of MCs compared with control samples. All samples from the later reparative stages of ARDS had increased numbers of myofibroblasts and procollagen type I producing cells. Increased numbers of MCs were seen in 55% of samples from the reparative stages. There was no significant shift in MC phenotype in the ARDS samples.

CONCLUSIONS—Increased numbers of myofibroblasts and procollagen type I producing cells were frequently found early in the course of ARDS. MC hyperplasia was unusual during this stage, but was often a feature of the later reparative stages. MCs do not appear to initiate fibroproliferation in ARDS.
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UMEÅ UNIVERSITY MEDICAL DISSERTATION
New series No 1097 ISSN 0346-6612 ISBN 978-91-7264-266-9
From the Department of Public Health and Clinical Medicine,
Respiratory Medicine and Allergy, Umeå University, Sweden
Ozone and Diesel Exhaust, Airway Signaling, Inflammation and
Pollutant Interactions Jenny Bosson, Umeå

Epidemiological evidence concerning the harmful health effects of air pollutants on the respiratory and cardiovascular systems has been accumulated over the last few decades. This is further supported by results from animal and in vitro studies demonstrating cellular and tissue damage after exposure to diesel exhaust as well as ozone. Human exposure studies have found clear associations between exposure to these oxidant air pollutants and airway neutrophilia.
The last two studies in the thesis address the important issue of the cumulative inflammatory airway effects of exposure to an urban pollution profile. When exposed to a sequential diesel exhaust and ozone exposure model analysis of inflammatory cells in induced sputum and BW showed an AMPLIFIED neutrophilia.

These novel findings reveal a clear ADDATIVE effect on the proximal airway inflammation when exposed in sequence to environmentally relevant levels of these air pollutants.
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F. J. Kelly1 and I. S. Mudway1
(1) Air Pollution and Health Research Group, School of Health & Life Sciences, Kings College London, London, United Kingdom, GB
Received: 28 December 2002 Revised: 1 January 2003 Accepted: 8 May 2003 Published online: 31 July 2003

Summary. Whilst performing its normal functions the lung is required to deal with a range of toxic insults. Whether these are infectious agents, allergens or air pollutants they subject the lung to a range of direct and indirect oxidative stresses.

In many instances these challenges lead to oxidative alterations of peptides and proteins within the lung. Measurement of protein oxidation products permits the degree of oxidative stress to be assessed and indicates that endogenous antioxidant defences are overwhelmed.

The range of protein oxidation products observed is diverse and the nature and extent of specific oxidation products may inform us about the nature of the damaging ROS and NOS. Recently, there has been a significant shift away from the measurement of these oxidation products simply to establish the presence of oxidative stress, to a focus on identifying specific proteins sensitive to oxidation and establishing the functional consequences of these modifications.
In addition the identification of specific enzyme systems to repair these oxidative modifications has lead to the belief that protein function may be regulated through these oxidation reactions. In this review we focus primarily on the soluble protein components of within the surface liquid layer in the lung and the consequence of their undue oxidation.
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Thorax 1998;53:823–829
Original articles
Fibroproliferation and mast cells in the acute respiratory distress syndrome Janice M Liebler, Zhenhong Qu, Brenda Buckner, Michael R Powers, James T Rosenbaum

Results

CLINICAL FEATURES OF STUDY POPULATION
DESCRIPTIVE IMMUNOHISTOCHEMISTRY
In the early, exudative stage of ARDS the injured tissue exhibited thickening of the alveolar septum, alveolar haemorrhage, and hyaline membrane formation. To identify myofibroblasts and type I collagen producing cells, slides were labelled with antibodies to alpha-smooth muscle actin (ASMA) and procollagen type I, respectively. Strong cytoplasmic staining for ASMA was found in thin spindle-shaped cells in the alveolar walls (fig 1A). These ASMA positive cells had the morphological appearance of myofibroblasts

Fibroproliferation and mast cells in the acute respiratory distress syndrome (ards) 825 fibroblasts. No ASMA staining was associated with capillaries, alveolar epithelial cells, or inflammatory cells. Cells that were immunoreactive for procollagen type I in the injured alveolar wall were also seen at this stage (fig1B). To determine whether there was a simultaneous increase in MC numbers, slides were also labelled with antibody to tryptase which identifies all human MCs.

Strong cytoplasmic immuno-localisation of tryptase was seen in a
few rounded cells in the alveolar septum (fig 1C). These tryptase positive cells had the morphological appearance of MCs. In the later reparative stages of lung injury alveolar spaces were frequently replaced with granulation tissue. Nests of loosely organised fibroblasts were often found. Most of the cells in these areas of developing fibrosis were immunoreactive for ASMA (fig 1D).

Procollagen type I positive cells were also seen in areas of active fibroproliferation (fig 1E). A modest increase in the number of tryptase positive MCs was identified at this stage (fig 1F). These
cells were often found along the edges rather than within the most fibrotic part of the lesions.

SEMIQUANTITATIVE ANALYSIS OF IMMUNOHISTOCHEMISTRY SLIDES
To determine whether there was a relationship between numbers of MCs and the development of fibroproliferation, a semiquantitative
analysis was carried out. MC scores from the normal tissues examined were all equal to 1 (fig 2). Although there was a significant increase in the mean MC score in lung tissue from the
reparative stages of ARDS (ARDS (R) which includes samples with mixed/organising and fibroproliferative findings) compared with lung tissue from the early stages of ARDS (ARDS (E) which includes samples with exudative findings only), the mean scores from both the ARDS (E) and ARDS (R) samples were not.

Figure 1 Representative photomicrographs of lung tissue with (A–C) features of the early exudative phase of ARDS (ARDS (E)) and (D–F) features of the reparative stage of ARDS (mixed/organising or fibroproliferative features; ARDS (R)).

Immunohistochemical localisation (indicated by red colour) of á-smooth muscle actin (ASMA), procollagen type I, and tryptase is shown as described in the Methods section. ASMA positive myofibroblasts (A) and procollagen type I producing cells (B) are present in the alveolar walls of the injured tissue in the early exudative stage. Few tryptase positive MCs are present at this stage (C). By comparison, nests of ASMA positive myofibroblasts (D) and procollagen type I producing cells (E) are present in samples of the later reparative stage.

Increased numbers of MCs are found in areas of fibroproliferation (F). All slides processed with alkaline phosphatase conjugated to avidin-biotin complex with Fast Red as chromogen. Gill’s haematoxylin was used as the counterstain. Magnification 400´ for (A), (B), (D), and (E) and 250´ for (C) and (F).826 Liebler, Qu, Buckner, et al significantly different from normal tissue. Of note, MC scores were raised (>5) in all samples from patients with end stage IPF, far exceeding values obtained from any of the ARDS samples.
In the normal lung at least 90% of MCs exist as MCT subset MCs and the remainder as MCTC subset cells. 14 To determine whether
there was a shift in the distribution of MC subsets with different stages of ARDS, dual labelling of slides with tryptase and chymase
antibodies was undertaken. We confirmed the predominance of MCT cells in normal lung tissue (mean (SE) MCTC subset cells 1.5 (0.5)%; fig 3). There was a marked increase in the MCTC subset in the end stage IPF samples (mean (SE) 49 (10)%). Although there was a trend towards an increased percentage of MCTC subset MCs in the ARDS (R) samples (5.9 (2.9)%), the percentage was not significantly different from normal samples.

Previous investigators have shown that only airway and vascular smooth muscle cells exhibit immunoreactive ASMA in normal
tissue while no immunoreactive ASMA was noted in alveolar walls. 15 We also found that ASMA staining in normal lung parenchyma was minimal (ASMA score <5). Increased numbers of ASMA positive cells were found in 80% of the ARDS (E) and 100% of the ARDS (R) samples studied (defined as ASMA score >10), as shown in fig 4A. The mean ASMA score for the ARDS (E)(Early) samples was more than three times higher and the ARDS (R)(Reparative) samples more than five times higher than control tissue (figs 4B and 4C).

Mesenchymal cells actively involved in collagen type I synthesis are identified with the anti-procollagen type I antibody. We found
minimal immunoreactive procollagen type I localised to alveolar structures in normal tissue (procollagen type I scores <5).
Increased numbers of procollagen type I producing cells were Figure 2 Relationship between individual mast cell (MC) scores and stage of ARDS using pathological criteria alone. A semiquantitative method was used to determine the MC score in lung parenchyma as described in the Methods section. Horizontal lines represent means of each group.

There was no significant difference between MC scores from normal tissue and from samples from the early exudative phase of ARDS (ARDS (E)) or from the later reparative phase (ARDS (R)). There was a significant difference in MC score between normal tissue and idiopathic pulmonary fibrosis (IPF) samples (p<0.05).
MC score

Normal ARDS (E) ARDS (R) IPF
Figure 3 Percentage of mast cells (MCs) in lung parenchyma expressing the MCTC phenotype in individual samples using pathological criteria alone. Horizontal lines represent means of each group. There was no significant difference in the percentage of MCTC MCs from normal tissue and from samples from the early exudative phase of ARDS (ARDS (E)) or from the later reparative phase (ARDS (R)). There was a significant difference in thepercentage of MCTC MCs between normal tissue and idiopathic pulmonary fibrosis (IPF) samples (p<0.05).
Percentage MCTC MC

Normal ARDS (E) ARDS (R) IPF Figure 4 (A) Percentage of samples with increased á-smooth muscle actin (ASMA), procollagen type I and mast cell (MC) scores according to stage of ARDS. Scores for ASMA and procollagen type I stained slides of >10 were defined as increased (normal tissue scores were <5) and MC scores of >2 were defined as increased (normal tissue scores = 1). Individual ASMA, procollagen type I and MC scores for samples with characteristics of (B) the early exudative stage of ARDS (ARDS (E)) and (C) the later reparative stage (ARDS (R)). Horizontal lines represent means of each group.

Fibroproliferation and mast cells in the acute respiratory distress syndrome 827 found in 50% of the ARDS (E) and 100% of the ARDS (R) samples studied (defined as procollagen type I score >10), as shown in fig 4A. The mean procollagen type I score was less than twice as high in ARDS (E) samples but nearly four times higher in the ARDS (R) samples than in control tissue (figs 4B and 4C). As also shown in fig 4A, there was an increase in MC scores (defined as MC score >2) in only 17% of samples from patients with ARDS (E).

The number of patients with increased MC scores rose to 55% in the ARDS (R) samples. However, the change in MC numbers was
modest compared with the large increases in ASMA and procollagen type I positive cells (figs 4B and 4C).

The relationship between myofibroblast infiltration and MC hyperplasia for all ARDS samples regardless of pathological diagnosis is shown in fig 5A. High ASMA scores were present at all levels of MC infiltration. By comparison, there was a significant increase in the procollagen type I score associated with MC scores of >2 (p <0.05), as shown in fig 5B.

Discussion
Although the exudative stage of ARDS is dominated by findings of haemorrhage and oedema, increased numbers of myofibroblasts were present in 80% of samples taken during that early injury phase. Similarly, increased numbers of procollagen type I producing cellswere found in half the samples examined. MC hyperplasia was found in only 17% of the exudative stage samples, suggesting that theinfiltration of MCs is not a primary event.

Thus, the fibroproliferative response appears to be initiated early after the acute injury in many patients with ARDS and occurs without an initial increase in MCs.

All samples taken from the later reparative stages of ARDS showed increased numbers of myofibroblasts and procollagen type I producing cells. Increased numbers of MCs were found in only half of these same samples. There was no significant difference in the percentage of MCs expressing the MCTC phenotype in the ARDS samples compared with normal tissue, although there was a trend towards an increased percentage in the later reparative stage samples. MC hyperplasia was most closely related to the presence of increased numbers of procollagen type I producing cells.

Type I collagen, thicker and more resistant to degradation than type III collagen, is generally found in more advanced fibrotic lesions.10 This relationship between MCs and procollagen type I producing cells further suggests that MC infiltration is a later event in fibrogenesis. .We were also interested in learning how the relationship between MCs and fibroproliferation in ARDS compared with that seen in the advanced fibrosis of end stage IPF. In no case did lung tissue from ARDS patients demonstrate the profound MC hyperplasia seen in the IPF samples. In addition, there was a pronounced shift in MC phenotype in the IPF samples, with a eight times greater proportion of MCs of the MCTC subset compared with samples from patients with reparative stage ARDS. Of interest, MCTC subset MCs have been described as “non-immune systemrelated” in that they are more often associated with angiogenesis and tissue remodelling than with allergic disorders.16 Although the process of fibroproliferation in ARDS and IPF shares some similarities, it is also different in important ways such as initiating factors, time course, and possible contribution of mediators from non-pulmonary organ systems. It is unknown whether the differences in MCs are due to different disease mechanisms or merely reflect a difference in the relative maturity of the fibrotic process.

Previous studies using animal models havesupported a role for MCs in the pathogenesisof fibrosis. Using an experimental model ofbleomycin induced pulmonary fibrosis in therat, Goto et al found that MC density was below baseline at day 7, but increased markedly by day 14 when early fibrotic lesions were present. MC density continued to rise for the duration of the study.17 Other investigators have found that MC-deficient animals are less susceptible than controls to lung injury and fibrosis under experimental conditions.18 19 Apossible explanation for these findings is that MCs are not important in the initiation of fibroproliferation, but are recruited by cells which have already set the stage for mesenchymal cell influx and increased matrix deposition.

MCs may then promote the continuation of the
fibrotic process. Figure 5 (A) Relationship between mean mast cell (MC) scores and mean á-smooth muscle actin (ASMA) scores in
ARDS samples regardless of pathological diagnosis. The differences between ASMA scores and the different MC scores were not significant. (B) Relationship between mean MC scores and procollagen type I scores in ARDS samples, regardless of pathological diagnosis. *p<0.05. 828 Liebler, Qu, Buckner, et al

There are several limitations to studying fibroproliferation and MCs in ARDS patients using archived lung tissue. Individual patients were not studied prospectively and could not be sampled serially over the course of their disease process. Study of the dynamic process of MC degranulation in fixed lung tissue is hampered by the inability to measure MC degranulation products (histamine, proteases, others) in biological fluids. However, several investigators have supported the ability of histological techniques to identify both intact and degranulating MCs.11 20 21 Since it is difficult to obtain lung samples immediately after the initiation of mechanical ventilation in patients with ARDS, very early time points (within the first few hours) in the course of ARDS have been missed. It would be interesting in future studies to look for evidence of MC degranulation—for example, tryptase or histamine levels—in bronchoalveolar lavage fluid from patients at the early time points. Our study population included predominantly patients who died with ARDS and may not provide information regarding the potential reversibility of this process. Previous investigators have learned that features of fibroproliferation in patients with ARDS are associated with a poor outcome.22 23 However, our tissue samples provide some clues as to the possible temporal relationship between MCs and fibroproliferation.

In summary, we found that markers of fibroproliferation were often present early in the course of ARDS. Fibroproliferation was initiated before increased numbers of MCs were evident.We speculate that MCs do not initiate fibrogenesis in ARDS, but may support the continuation of the process by releasing potent mediators into the local environment.

Dr Rosenbaum is the recipient of a Senior Scholar Award from
Research to Prevent Blindness, New York and Dr Powers is the
recipient of a Physician Scientist Award from the National Eye
Institute. Lung tissue from the University of Texas Health Science
Center at San Antonio was obtained as part of the NIH
grants HL-23578 and HL-07221. The authors would like to
thank Joshua Eubanks for his technical support during this
project. Supported by the American Lung Association of Oregon and the Oregon Health Sciences Foundation Donor Fund.

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_________________________________________
Οxidative stress and its control in the lung
Thematic Series
Correspondence to:
Stelios Loukides, MD FCCP
Lecturer Respiratory Medicine,
University of Athens Medical School
2 Smolika street
Τel.: +30 210 8954603, +30 6944 380549
Fax: +30 210 7770423, +30 210 5831184

SUMARY. Due to its large surface area and its rich blood supply,
the lung is susceptible to oxidative injury by many reactive oxygen
species and free radicals. The main sources of oxidants affecting the lung include external agents (smoke, radiation, carcinogens, drugs,
ozone, hyperoxia) and cellular mechanisms (inflammatory cells such as neutrophils, eosinophils, macrophages, fibroblasts, endothelial cells, xanthine and NADPH oxidases). Via these sources oxygen and nitrogen reactive species are produced, which exert the final harmful effect of cell damage. The major oxidative agents are the superoxide anion, hydrogen peroxide, the hydroxyl radical, nitric oxide, etc. Antioxidants help the lung to ward off the consequences of the oxidative injury. Antioxidant defenses include non-enzymatic agents (vitamins C and E, beta-carotene, uric acid) and enzymes (dismutase, catalases and peroxidases). New research has revealed the activity in antioxidant defense at a more subtle level of low molecular weight proteins such as oxygenase-heme, thioredoxins, etc. The susceptibility of the lung to oxidant injury depends mainly on the degree of its ability to upregulate the antioxidant defenses, which means that the various lung diseases attributed to oxidative injury could possibly be controlled by the antioxidant mechanisms at the cellular level or even at the level of gene expression. Antioxidant defense may be present at both cell and mRNA expression level, but antioxidant activity is the critical factor in the development and progression of lung disease. Pneumon 2007; 20(3):289-292
__________________________________________

Sadatomo Tasaka
Division of Pulmonary Medicine, Keio University School of Medicine, Tokyo, Japan.
Fumimasa Amaya
Department of Intensive Care and Anesthesiology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Satoru Hashimoto
Department of Intensive Care and Anesthesiology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Akitoshi Ishizaka
Division of Pulmonary Medicine, Keio University School of Medicine, Tokyo, Japan.

The acute respiratory distress syndrome (ARDS) is a disease process that is characterized by diffuse inflammation in the lung parenchyma and resultant permeability edema. The involvement of inflammatory mediators in ARDS has been the subject of intense investigation, and oxidant-mediated tissue injury is likely to be important in the pathogenesis of ARDS. In response to various inflammatory stimuli, lung endothelial cells, alveolar cells, and airway epithelial cells, as well as alveolar macrophages, produce reactive oxygen species (ROS) and reactive nitrogen species (RNS). In addition, the therapeutic administration of oxygen can enhance the production of these toxic species. As the antioxidant defense system, various enzymes and low-molecular weight scavengers are present in the lung tissue and epithelial lining fluid. In addition to their contribution to tissue damage, ROS and RNS serve as signaling molecules for the evolution and perpetuation of the inflammatory process, which involves genetic regulation.

THE PATTERN OF GENE EXPRESSION MEDIATED
BY OXIDANT-SENSITIVE TRANSCRIPTION FACTORS IS A CRUCIAL COMPONENT OF THE MACHINERY THAT DETERMINES CELLULAR RESPONSES TO OXIDATIVE STRESS.
This review summarizes the recent progress concerning how redox status can be modulated and how it regulates gene transcription during the development of ARDS, as well as the therapeutic implications.
__________________________________________

OZONE LAYER - Most ozone (about 90%) resides in a layer that begins between 6 and 10 miles above the Earth’s surface and extends up to about 30 miles. This region of the atmosphere is called the stratosphere from aboout 15-35 miles above the earth’s surface . The ozone in this region is commonly known as the ozone layer.

The remaining ozone is in the lower region of the atmosphere, which is commonly called the troposphere. zero to 15 miles above the Earth’s surface.

The ozone layer around the earth is getting thinner and thinner. Ozone is a naturally occuring gas whose chemical symbol is O3. This is not that much different from the oxygen that we breathe, O2. Ozone has just one more oxygen atom than the oxygen in the air we breathe normally.

However, this one tiny difference can make a big effect on our planet. While oxygen in its O2 form is breathable, O3 is harmful to people animals if inhaled. However, O3 ozone stays in a layer around the earth.

Meanwhile, there is the sun doing it’s job of providing light and heat. We can only see a certain range of light, from red to violet, and we see it as the colors of the rainbow, ROYGBIV- red, orange, yellow, green, blue, indigo and viloet.

However, there is also light we can’t see, outside of what our eyes can detect. On the left to red in wave length is the invisible infra-red, which is actually what heats the earth. On the other end of the rainbow, just past violet in wave length, is a light called ultraviolet. We normally know this type of light as the black light, or the glow in the dark light. This light is harmful to life on earth as we know it, and can kill it if we get exposed to it too much. This is where ozone plays its part.

Ozone absorbs these ultraviolet rays before it reaches the earth. When it absorbs these harmful rays, a chemical reaction occurs where the ozone is split into oxygen gas (O2) and a free oxygen atom (O).

Normally, the parts immediately rejoin together to form ozone again. This is where man and his meddling around steps in. People have made a group of chemicals called ChloroFluoroCarbons, or Cl-Fl-Cs. ClFlCs are found in many items we use, from the air conditioners in cars, to the refrigerators and freezers in our homes, to the hair sprays we use to keep our hair in place, and even to medicinal products such as asthma inhalers. When we use this gas, it rises into the air, and also reacts with ultraviolet light.

Cl-Fl-C + ULTRAVIOLET LIGHT = Fl-C + Cl-
There is an extra chlorine atom after this reaction. This atom wreaks havoc on our ozone layer. Instead of the O2 and O hooking up after the reaction, instead the O hooks up to the chlorine atom, since the O has a stronger attraction to the chlorine than to the oxygen atom.
Cl- + O+ = ClO

The new compound of ClO does absolutely nothing for us; it doesn’t block the harmful ultraviolet (UV) rays, and allows some more to pass to the earth. Since Cl-Fl-Cs were invented this century, more and more ozone is rendered ineffective.

This seems to happen all collect in two areas: the North and South Poles. ClO in the poles is rising, and the ozone levels are dropping to critically low levels. Thinning like this is already occuring over the United States. A complete hole over the U.S. or any populated area would be a complete disaster.

The U.S., Europe, Japan, and the former Soviet Union are large users of Cl-Fl-Cs. It isn’t surprising then that the worst thinning of the ozone is occuring directly over these countries.
___________________________________________

ABOUT ATMOSPERIC AND GROUND LEVEL OZONE
Chem Res Toxicol. 2002 Jul;15(7):896-906.

Oxidized phospholipids derived from ozone-treated lung surfactant extract reduce macrophage and epithelial cell viability.
Uhlson C, Harrison K, Allen CB, Ahmad S, White CW, Murphy RC.
Division of Cell Biology, Department of Pediatrics, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, Colorado 80206, USA.

“Ozone is known to be a highly toxic gas present in the urban air which exerts its effect on pulmonary tissue through its facile chemical reactions with target molecules in the airway. One of the first barriers encountered by ozone is epithelial lining fluid which contains pulmonary surfactant rich in glycerophosphocholine lipids.
The reaction of ozone with calf lung surfactant extract was found to result in the production of 1-palmitoyl-2-(9′-oxo-nonanoyl)-glycerophosphocholine (16:0a/9-al-GPCho) as an expected product of the ozonolysis of abundant unsaturated phospholipids containing unsaturated fatty acyl groups with a double bond at carbon-9.
This oxidized phospholipid was identified as a biologically active product in that it reduced elicited macrophage viability by necrosis with an ED(50) of 6 microM. Further studies of the biological activity of 16:0a/9-al-GPCho revealed that concentrations from 100 to 200 nM initiated apoptosis in pulmonary epithelial-like A549 cells as assessed by TUNEL staining, nuclear size, and caspase-3 activation with loss of viability indicated by reduction of mitochondrial dehydrogenase activity.

The release of IL-8, a neutrophil chemokine, from A549 cells was also stimulated by 50-100 nM 16:0a/9-al-GPCho. Exposure of calf lung surfactant to low levels of ozone (62.5, 125, and 250 ppb) for various time periods from 2 to 48 h in a feedback-regulated ozone exposure chamber resulted in a dose- and time-dependent increase in the formation of 16:0a/9-al-GPCho as measured by a specific and sensitive LC/MS/MS assay. The quantity of this biologically active chain-shortened glycerophosphocholine lipid generated even at 125 ppb ozone for 2-4 h (50-100 nM) was consistent with this product mediating the toxic effects of ozone on cells in contact with surfactant.”

PMID: 12118999 [PubMed - indexed for MEDLINE]